Dan Wells,
Professor Department of Biology and Biochemistry University of Houston

Multiple Hereditary Exostoses (MHE) is an autosomal dominant skeletal disorder most frequently caused by mutations in the EXT1

MHE affects proper development of endochondral bones, such that all affected individuals present with exostoses adjacent to the
growth plate of long bones, while some individuals exhibit additional bone deformities. EXT1 functions as a heparan sulfate (HS)
co-polymerase, and when defective causes improper elongation of glycosaminoglycan side chains on core proteins of HS

Although analysis of heterozygous EXT1-deficient mice has failed to reveal any significant gross morphological variations in skeletal
development, significant alterations in molecular signaling occur in the developing long bones.

Our results indicate that defects in EXT1 and the resulting reduction in HS lead to enhanced Indian Hedgehog diffusion causing an
increase in chondrocyte proliferation and delayed hypertrophic differentiation.
Dr. Wells serves on the Scientific and Medical Advisory Board of the MHE Research Foundation
Research authored by Dr. Wells
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Dan Wells, Ph.D, research
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2009 Conference abstract
Perspectives on the Genetics of Multiple Hereditary Exostosis

Dan Wells
President UH Faculty Senate, and Professor Department of Biology and Biochemistry, University of Houston, Houston TX 77204.


The first description of multiple exostoses in several members of the same family is generally accredited to Boyer in 1814.  Since
then close to 1000 reports have been published describing a hereditary form of multiple exostoses. The first comprehensive
genetic description of the disease in modern times was done by Solomon, 1964 who analyzed 42 cases. In this study, Solomon
established Multiple Hereditary Exostoses as autosomal dominant syndrome with essentially 100% penetrance. Initial evidence for
the chromosomal location of MHE came from its association with Langer-Giedion Syndrome (tricho-rhino-phalangeal syndrome
type 2). In addition to other phenotypes, individuals with LGS had multiple exostoses identical to those seen in MHE. Various
reports, summarized by Bulher and Malik, 1984, associated LGS with deletions in 8q24.1. Formal conformation of this genetic
location came in 1993 by Cook et al., who performed a genetic linkage analysis on 11 families with MHE.

A side result of this study indicated that there was at least one other chromosomal location that could cause MHE. This was
quickly located on chromosome 11 by Wu et al. 1994.  In 1995, the EXT1 gene was positionally cloned and sequenced (Ahn et al.,
1995) followed by the identification of the EXT2 gene (Stickens, 1996; Wuyts 1996). Although the two genes showed some
structural similarities, their protein sequences gave few clues as to their function. The first indications of function of the EXT genes
came from a series of papers in 1998 (McCormick et al., 1998; Lin et al., 1998; Lind et al., 1998; Simmons et al., 1999).
McCormick et al. (1998) lead the way somewhat by accident. Using an eloquent cell culture technique to look for genes involved in
the biosynthetic pathway of GAGs, they identified EXT1 as an ER-resident type II transmembrane glycoprotein that altered the
synthesis and display of cell surface heparan sulfate glycosaminoglycans (GAGs) and Lind et al. (1998) further showed EXT2 had
similar capabilities. A suggestion as to how heparan sulfate GAGs function in abnormal bone growth came with the discovery of
the Drosophila EXT1 homolog, tout velu (ttv). Bellaichie et al. (1998) showed that ttv was required for the diffusion of hedgehog
in Drosophila. Lin et al. (1999) use EXT1 deficient mice to show that heparan sulfate GAGs affected the binding of hedgehog to
the cell surface and disrupted the expression of a number of embryonic markers.

Over the past 10 years, research on MHE appears to have focused on three main areas, tumoragenesis, endochondral bone
growth, and model systems (Hecht, et al., 2002; Han et al., 2004; Koziel et al., 2004; Hilton et al., 2005; Stickens et al., 2005;
Hameetman et al., 2007; Kitagawa et al., 2007; Clement et al., 2008). Some key aspects of these studies will be discussed in light
of the where the field is currently and what it will be its focus as we move into the next decade. Some old questions need to be
put to rest (such as "loss of heterozygosity" and the "genesis of tumors") while others need to be explored more deeply (such as
"is this just a bone disease?").
Photo's taken during the
Third International MHE Research Conference
Compound heterozygous loss of Ext1 and Ext2 is sufficient for formation of multiple exostoses in mouse ribs and long
Zak BM, Schuksz M, Koyama E, Mundy C, Wells DE, Yamaguchi Y, Pacifici M, Esko JD.
Bone. 2011 May 1;48(5):979-87. Epub 2011 Feb 15.

To read
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Multiple Hereditary Exostoses (MHE) syndrome is caused by haploinsufficiency in Golgi-associated heparan sulfate polymerases
EXT1 or EXT2 and is characterized by formation of exostoses next to growing long bones and other skeletal elements. Recent
mouse studies have indicated that formation of stereotypic exostoses requires a complete loss of Ext expression, suggesting that
a similar local loss of EXT function may underlie exostosis formation in patients. To further test this possibility and gain greater
insights into pathogenic mechanisms, we created heterozygous Ext1(+/-) and compound Ext1(+/-)/Ext2(+/-) mice. Like
Ext2(+/-) mice described previously (Stickens et al. Development 132:5055), Ext1(+/-) mice displayed rib-associated
exostosis-like outgrowths only. However, compound heterozygous mice had nearly twice as many outgrowths and, more
importantly, displayed stereotypic growth plate-like exostoses along their long bones. Ext1(+/-)Ext2(+/-) exostoses contained
very low levels of immuno-detectable heparan sulfate, and Ext1(+/-)Ext2(+/-) chondrocytes, endothelial cells and fibroblasts in
vitro produced shortened heparan sulfate chains compared to controls and responded less vigorously to exogenous factors such
as FGF-18. We also found that rib outgrowths formed in Ext1(f/+)Col2Cre and Ext1(f/+)Dermo1Cre mice, suggesting that ectopic
skeletal tissue can be induced by conditional Ext ablation in local chondrogenic and/or perichondrial cells. The study indicates that
formation of stereotypic exostoses requires a significant, but not complete, loss of Ext expression and that exostosis incidence
and phenotype are intimately sensitive to, and inversely related to, Ext expression. The data also indicate that the nature and
organization of ectopic tissue may be influenced by site-specific anatomical cues and mechanisms.

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